1. Technical Field
This invention relates to therapy for enhancing repair of neural injury in the central nervous system or the peripheral nervous system.
2. Background
Neural injury caused by physical trauma, ischemia, or disease can result in profound disability or death. Such disabilities, which may be physical and/or mental, include loss of movement, impaired sensory perception, loss of cognitive functions, seizures, and emotional and personality disorders. Given the incidence of death and the prevalence and possible severity of survivors"" disabilities, neural injury takes a heavy toll on individuals and society. Accordingly, there is a need for treatments which facilitate the repair of damaged nerves and neuronal pathways. At present, there is no effective treatment for central nervous system (CNS) injuries.
Brain physical trauma, spinal cord compression or transection, ischemia, or surgery cause hypoxia which initiates a cascade of molecular events leading to neural injury (Liu, X. Z. et al., Neuronal and glial apoptosis after traumatic spinal cord injury, J. Neurosci., 17:5395-5406 (1997); Olsson, Y. et al., Release of endogenous neurochemicals may increase vascular permeability, induce edema and influence cell changes in trauma to the spinal cord, Progress in Brain Res., 91:197-203 (1992); Crowe, M. J. et al., Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys, Nature Med., 3:73-76 (1997)). Despite receiving medical attention, many patients die in the first few days following a serious CNS injury. For those patients that survive their injuries, prognosis depends on the ability of the remaining neurons to adapt new functions because, with current technology, neuronal connectivity is rarely restored. Because neural adaptation is slow and frequently incomplete, the potential benefit of a treatment which facilitates neural repair and the re-establishment of neuronal connectivity would be tremendous as would the benefit provided by a treatment that reduces the probability that a patient will die during the critical post-injury period.
Neurons in the peripheral nervous system can regenerate and re-innervate their targets. However, scar tissue that forms as a result of the injury can obstruct the growth of regenerating peripheral nerves and interfere with recovery of neural function. Because repair of neural injury can be facilitated by inhibiting scar formation, there is a need for a treatment to minimize scar formation in the peripheral nervous system.
Regeneration of nerves in the mammalian CNS is more limited. In the adult mammalian CNS, neural regeneration was thought nearly impossible until recently (Snell, L. and Schwab, M. E., Sprouting and regeneration of lesioned cortical spinal tract fibers in the adult rat spinal cord, Eur. J. Neurosci., 5:1156-1161 (1993); Cheng, H. et al., Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function, Science, 273:510-513 (1996); Young, W., Spinal cord regeneration, Science, 273:451 (1996); Olson, L., Regeneration in the adult central nervous system: Experimental repair strategies, Nature Med., 3(12):1329-1335 (1997); Li, Y., et al., Repair of adult rat cortical spinal tract by transplant of olfactory and ensheathing cells, Science, 277:2000-2002 (1997)). Since adult mammalian CNS neurons have been shown to be capable of growing and developing synaptic connections when placed in a different setting, it has been hypothesized that the CNS contains inhibitors of neuronal regeneration. Neuronal growth in the CNS may also be retarded by gliosis, a process in which glial scars are formed in the healing CNS as a result of the proliferation of astrocytes and microglia and the infiltration of macrophages. Posttraumatic epilepsy, which can arise up to several years after head trauma, is also associated with glial cerebromeningeal scars (McNamara, J. O., Cellular and molecular basis of epilepsy, J. Neurosci., 14:3413-3416 (1994)). Since minimizing gliosis can both facilitate neuronal regeneration and decrease the likelihood of posttraumatic epilepsy, there is a need for treatments which inhibit gliosis.
The failure of persons with CNS injuries, particularly spinal cord injuries, to regain neural function is at least partially due to steric interference by gliosis and subsequent scar formation. There is a need for a treatment to facilitate repair of CNS injuries by minimizing gliosis and scarring. The need is particularly great for a treatment that, in addition to facilitating healing of recent neural injuries, could aid in the restoration of neural function in a person with a pre-existing neural injury.
The present invention is a method of treating neural injury by administering a GBS toxin, a nontoxic polysaccharide derived from group B xcex2-hemolytic Streptococcus bacteria.
One aspect of the present invention is the administration of a GBS toxin to a patient with a neural injury to promote the re-establishment of neuronal connectivity. The present invention demonstrates that GBS toxin administration facilitates enhanced transfer of electrical impulses across a site of neural damage. GBS toxin-mediated enhancement of neuronal connectivity is functionally significant: animals treated with GBS toxin regained the ability to walk within a few days of neuronal injury whereas untreated animals with identical injuries remained paralyzed.
Another aspect of the present invention is the administration of a GBS toxin to minimize scar formation in patients with neuronal injury. Minimizing scar formation allows more complete recovery of neuronal connectivity. In addition, by reducing gliosis, GBS toxin administration to patients with head trauma reduces the likelihood of posttraumatic epilepsy and other complications.
A third aspect of the invention is the administration of a GBS toxin to increase the probability of a patient""s survival following CNS injury.
A fourth aspect of the invention is the administration of a GBS toxin to minimize formation of new scars following surgical excision of existing scar tissue associated with a preexisting neural injury.
An article of manufacture including GBS toxin, and particularly CM101, along with instructions for treatment, and a method of making the article are also disclosed.
According to the present invention, GBS toxin may be used to improve the quality of the healing process in both the CNS and the peripheral nervous system.